As part of a complex ensemble of hematopoietic regulators, HOXA9 helps maintain the balance between hematopoietic stem/progenitor cell (HSPC) self-renewal and myeloid/lymphoid cell differentiation in the bone marrow. Several genetic mutations observed in acute myeloid leukemia (AML) patients are associated with aberrant upregulation of HOXA9, thus disrupting the hematopoietic balance towards leukemogenesis. Altogether, HOXA9 is overexpressed in ~2/3rd of AMLs. Our preliminary data suggest a molecular interplay occurring on chromatin between HOXA9 and OGT, an O-linked N-acetyl glucosamine transferase, during HOXA9-driven leukemogenesis. In this R01 project, we propose to characterize the molecular mechanisms in which these proteins are involved to govern hematopoietic development and how disruptions of these molecular mechanisms can lead to leukemogenesis. Their impact on chromatin remodeling and their role in defining the fate of hematopoietic cells in the bone marrow will be investigated using cell-based and in vivo models of leukemogenesis. Our project should offer the means to manipulate those molecular mechanisms in leukemia patients for therapeutic benefit.